Abstract
Multidrug-resistant (MDR) pathogens pose a well-recognized global health threat that demands effective solutions; the situation is deemed a global priority by the World Health Organization and the European Centre for Disease Prevention and Control. Therefore, the development of new antimicrobial therapeutic strategies requires immediate attention to avoid the ten million deaths predicted to occur by 2050 as a result of MDR bacteria. The repurposing of drugs as therapeutic alternatives for infections has recently gained renewed interest. As drugs approved by the United States Food and Drug Administration, information about their pharmacological characteristics in preclinical and clinical trials is available. Therefore, the time and economic costs required to evaluate these drugs for other therapeutic applications, such as the treatment of bacterial and fungal infections, are mitigated. The goal of this review is to provide an overview of the scientific evidence on potential non-antimicrobial drugs targeting bacteria and fungi. In particular, we aim to: (i) list the approved drugs identified in drug screens as potential alternative treatments for infections caused by MDR pathogens; (ii) review their mechanisms of action against bacteria and fungi; and (iii) summarize the outcome of preclinical and clinical trials investigating approved drugs that target these pathogens.
Highlights
Bacteria and fungi are highly efficient in acquiring antimicrobial resistance encoded by genomic changes ranging in scale from point mutations, through the assembly of preexisting genetic elements, to the horizontal import of genes from the environment (Kung et al, 2010; Cowen et al, 2015; Yelin and Kishony, 2018)
Compounding the problem of antimicrobial resistance is the immediate threat of a reduction in the discovery and development of new antibiotics, the dangers of which have recently been made clear by the World Health Organization (WHO) (Tacconelli et al, 2018) and other European institutions (O’Neill, 2016; Årdal et al, 2018)
Binding to the two essential EF-hand proteins calmodulin 1 (Cam1) and calmodulin-like protein (Cml) and prevention of Cam1 from binding to its well-characterized substrate calcineurin Binding to the two essential EF-hand proteins calmodulin (Cam1) and calmodulin-like protein (Cml) and prevention of Cam1 from binding to its well-characterized substrate calcineurin Binding to PhzB2 which is involved in the production of pyocyanin, a pigment related with the virulence of P. aeruginosa Inhibition of undecaprenyl diphosphate synthase involved in the synthesis of teichoic acid wall Inhibition of filamentation Inhibition of biofilm formation and quorum sensing Inhibition of filamentation
Summary
The development of new antimicrobial therapeutic strategies requires immediate attention to avoid the ten million deaths predicted to occur by 2050 as a result of MDR bacteria. The time and economic costs required to evaluate these drugs for other therapeutic applications, such as the treatment of bacterial and fungal infections, are mitigated. The goal of this review is to provide an overview of the scientific evidence on potential non-antimicrobial drugs targeting bacteria and fungi. We aim to: (i) list the approved drugs identified in drug screens as potential alternative treatments for infections caused by MDR pathogens; (ii) review their mechanisms of action against bacteria and fungi; and (iii) summarize the outcome of preclinical and clinical trials investigating approved drugs that target these pathogens
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